tbuckley/cabot-search huggingface dataset:
Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis
Authors: Jun Li, Shaobo Hu, Henry W B Johnson, Christopher J Kirk, Peng Xian, Yanping Song, Yuan Li, Nan Liu, Marcus Groettrup, Michael Basler
Journal: Cardiovascular Research (2022)

Abstract Aims The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit to prevent immune-mediated vascular allograft rejection and TA is not clear. Methods and results The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (β5i) and LMP2 (β1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T-cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of immunoglobulin G-secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement, and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA. Conclusions We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection.
KIAA1429 promotes tumorigenesis and gefitinib resistance in lung adenocarcinoma by activating the JNK/ MAPK pathway in an m6A-dependent manner
Authors: Xi Lin, Rongyi Ye, Zhiming Li, Bingli Zhang, Yuji Huang, Jiaxin Du, Bo Wang, Hao Meng, Hongyi Xian, Xingfen Yang, Xin Zhang, Yizhou Zhong, Zhenlie Huang
Journal: Drug Resistance Updates (2022)

Non-small cell lung cancer is the leading cause of cancer related mortality worldwide, and lung adenocarcinoma (LUAD) is one of the most common subtypes. The role of N6-methyladenosine (m6A) modification in tumorigenesis and drug resistance in LUAD remains unclear. In this study, we evaluated the effects of vir-like m6A methyltransferase-associated protein (KIAA1429) depletion on proliferation, migration, invasion, and drug resistance of LUAD cells, and identified m6A-dependent downstream genes influenced by KIAA1429. We found that KIAA1429 activated Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway as a novel signaling event, which is responsible for tumorigenesis and resistance to gefitinib in LUAD cells. KIAA1429 and MAP3K2 showed high expression in LUAD patients' tissues. Knockdown of KIAA1429 inhibited MAP3K2 expression in an m6A methylation-dependent manner, restraining the progression of LUAD cells and inhibiting growth of gefitinib-resistant HCC827 cells. KIAA1429 positively regulated MAP3K2 expression, activated JNK/ MAPK pathway, and promoted drug resistance in gefitinib-resistant HCC827 cells. We reproduced the in vitro results in nude mouse xenografted with KIAA1429 knockdown cells. Our study showed that the mechanism of m6A KIAA1429-mediated gefitinib resistance in LUAD cells occurs by activating JNK/ MAPK signaling pathway. These findings provide potential targets for molecular therapy and clinical treatment in LUAD patients with gefitinib resistance.
Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis
Authors: Josefin Soppert, Elisa Fabiana Brandt, Nicole Maria Heussen, Emona Barzakova, Lars Mathias Blank, Lars Kuepfer, Mathias Walter Hornef, Jonel Trebicka, Joachim Jankowski, Marie-Luise Berres, Heidi Noels
Journal: Clinical Gastroenterology and Hepatology (2022)

Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights.PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology.Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability.Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.
关于如何在疼痛性皮肤病和类风湿关节炎研究中测量疼痛，以确定未来化脓性汗腺炎试验中的疼痛测量的综述
Journal: British Journal of Dermatology (2022)

Abstract Linked Article: Hasan et al. Br J Dermatol 2022; 187:846–854.
Is cognitive reserve associated with the prevention of cognitive decline after stroke? A Systematic review and meta-analysis
Authors: Israel Contador, Patricia Alzola, Yaakov Stern, Alejandro de la Torre-Luque, Félix Bermejo-Pareja, Bernardino Fernández-Calvo
Journal: Ageing Research Reviews (2022)

To conduct a systematic review and meta-analyses of the effect of socio-behavioral cognitive reserve (CR) proxies on cognitive decline after stroke.Three journal search and indexing databases (PubMed, Scopus and Web of Sciences) were crossed to examine the scientific evidence systematically. In addition, meta-analytic techniques, using mixed-effect methods, were carried out to estimate the impact (pooled effect size) of CR proxies on either dementia incidence or cognitive decline after stroke.Twenty-two studies were included in the systematic revision, whereas nineteen of them were eligible for the meta-analysis. The findings showed that high education is associated with a decreased rate of post-stroke dementia. Moreover, other CR proxies (e.g., occupation, bilingualism or social interaction) demonstrate a protective effect against non-dementia cognitive decline after stroke, although some inconsistencies were found in the literature. Regarding the meta-analysis, occupational attainment and education) showed a protective effect against post-stroke cognitive impairment diagnosis in comparison with a mixed category of different CR proxies. Second, a main cognitive change effect was found, pointing to greater cognitive change after stroke in those with low vs. high CR.Our findings emphasize that CR may prevent cognitive decline after stroke, but this effect can be modulated by different factors such the CR proxy and individual characteristics such as age or type of lesion. The methodological divergences of the studies (i.e., follow-up intervals, cognitive outcomes) need unification to diminish external sources of variability for predicting rates of cognitive decline after stroke.
Deep brain stimulation of the nucleus basalis of Meynert modulates hippocampal–frontoparietal networks in patients with advanced Alzheimer’s disease
Authors: Yin Jiang, Tian-Shuo Yuan, Ying-Chuan Chen, Peng Guo, Teng-Hong Lian, Yu-Ye Liu, Wei Liu, Yu-Tong Bai, Quan Zhang, Wei Zhang, Jian-Guo Zhang
Journal: Translational Neurodegeneration (2022)

Abstract Background Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown potential for the treatment of mild-to-moderate Alzheimer’s disease (AD). However, there is little evidence of whether NBM-DBS can improve cognitive functioning in patients with advanced AD. In addition, the mechanisms underlying the modulation of brain networks remain unclear. This study was aimed to assess the cognitive function and the resting-state connectivity following NBM-DBS in patients with advanced AD. Methods Eight patients with advanced AD underwent bilateral NBM-DBS and were followed up for 12 months. Clinical outcomes were assessed by neuropsychological examinations using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale. Resting-state functional magnetic resonance imaging and positron emission tomography data were also collected. Results The cognitive functioning of AD patients did not change from baseline to the 12-month follow-up. Interestingly, the MMSE score indicated clinical efficacy at 1 month of follow-up. At this time point, the connectivity between the hippocampal network and frontoparietal network tended to increase in the DBS-on state compared to the DBS-off state. Additionally, the increased functional connectivity between the parahippocampal gyrus (PHG) and the parietal cortex was associated with cognitive improvement. Further dynamic functional network analysis showed that NBM-DBS increased the proportion of the PHG-related connections, which was related to improved cognitive performance. Conclusion The results indicated that NBM-DBS improves short-term cognitive performance in patients with advanced AD, which may be related to the modulation of multi-network connectivity patterns, and the hippocampus plays an important role within these networks. Trial registration ChiCTR, ChiCTR1900022324. Registered 5 April 2019—Prospective registration. https://www.chictr.org.cn/showproj.aspx?proj=37712
Host acid signal controls <i>Salmonella</i> flagella biogenesis through CadC-YdiV axis
Authors: Weiwei Wang, Yingying Yue, Min Zhang, Nannan Song, Haihong Jia, Yuanji Dai, Fengyu Zhang, Cuiling Li, Bingqing Li
Journal: Gut Microbes (2022)

Upon entering host cells, Salmonella quickly turns off flagella biogenesis to avoid recognition by the host immune system. However, it is not clear which host signal(s) Salmonella senses to initiate flagellum control. Here, we demonstrate that the acid signal can suppress flagella synthesis and motility of Salmonella, and this occurs after the transcription of master flagellar gene flhDC and depends on the anti-FlhDC factor YdiV. YdiV expression is activated after acid treatment. A global screen with ydiV promoter DNA and total protein from acid-treated Salmonella revealed a novel regulator of YdiV, the acid-related transcription factor CadC. Further studies showed that CadCC, the DNA binding domain of CadC, directly binds to a 33 nt region of the ydiV promoter with a 0.2 μM KD affinity. Furthermore, CadC could separate H-NS-ydiV promoter DNA complex to form CadC-DNA complex at a low concentration. Structural simulation and mutagenesis assays revealed that H43 and W106 of CadC are essential for ydiV promoter binding. No acid-induced flagellum control phenotype was observed in cadC mutant or ydiV mutant strains, suggesting that flagellum control during acid adaption is dependent on CadC and YdiV. The intracellular survival ability of cadC mutant strain decreased significantly compared with WT strain while the flagellin expression could not be effectively controlled in the cadC mutant strain when surviving within host cells. Together, our results demonstrated that acid stress acts as an important host signal to trigger Salmonella flagellum control through the CadC-YdiV-FlhDC axis, allowing Salmonella to sense a hostile environment and regulate flagellar synthesis during infection.
Effectiveness of Nonmydriatic Ultra-Widefield Retinal Imaging to Screen for Diabetic Eye Disease: A Randomized Controlled Trial (Clearsight)
Authors: Selina L. Liu, John R. Gonder, Ehsan Owrangi, Neil S. Klar, Irene M. Hramiak, Artem Uvarov, Jeffrey L. Mahon
Journal: Diabetes Care (2022)

OBJECTIVE Suboptimal diabetic eye disease screening is a major cause of preventable vision loss. Screening barriers include mydriasis and the need for dedicated screening appointments. The Clearsight trial assessed whether nonmydriatic ultra-widefield (NM UWF) screening on the day of a diabetes clinic visit improved detection of clinically important eye disease versus usual screening. RESEARCH DESIGN AND METHODS This single-center, randomized, parallel-group controlled trial was conducted at St. Joseph’s Health Care, London, Ontario, Canada. Adults with diabetes due for screening were randomized to same-day, on-site screening (NM UWF imaging) on the day of a scheduled diabetes clinic visit or usual screening (encouraged to arrange optometrist screening). The primary outcome was detection of actionable eye disease (AED), defined as the need for an ophthalmology referral or increased ocular surveillance. The primary analysis (modified intention-to-screen) compared the proportions of AED between groups within 1 year of enrollment. RESULTS Of 740 participants randomized between 7 March 2016 and 17 April 2019, 335 on-site screening and 323 usual screening participants met criteria for the primary analysis. More AED was detected in the on-site screening group than in the usual screening group (50 of 335 [14.9%] vs. 22 of 323 [6.8%]; adjusted odds ratio 2.51; 95% CI 1.49–4.36). The number needed to screen by on-site screening in order to detect 1 additional patient with AED was 13 (95% CI 8–29). CONCLUSIONS Same-day, on-site screening by NM UWF imaging increased the detection of clinically important diabetic eye disease versus usual screening. Integration of NM UWF imaging into routine diabetes clinic visits improved screening adherence and has the potential to prevent vision loss.
Empirical rescue treatment of<i>Helicobacter pylori</i>infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on<i>H. pylori</i>management (Hp-EuReg)
Authors: Diego Burgos-Santamaría, Olga P Nyssen, Antonio Gasbarrini, Dino Vaira, Ángeles Pérez-Aisa, Luís Rodrigo, Rinaldo Pellicano, Alma Keco-Huerga, Manuel Pabón-Carrasco, Manuel Castro-Fernandez, Doron Boltin, Jesus Barrio, Perminder Phull, Juozas Kupcinskas, Laimas Jonaitis, Inmaculada Ortiz-Polo, Bojan Tepes, Alfredo J Lucendo, José María Huguet, Miguel Areia, Natasa Brglez Jurecic, Maja Denkovski, Luís Bujanda, June Ramos-San Román, Antonio Cuadrado-Lavín, Judith Gomez-Camarero, Manuel Alfonso Jiménez Moreno, Angel Lanas, Samuel Jesús Martinez-Dominguez, Enrique Alfaro, Ricardo Marcos-Pinto, Vladimir Milivojevic, Theodore Rokkas, Marcis Leja, Sinead Smith, Ante Tonkić, György Miklós Buzás, Michael Doulberis, Marino Venerito, Frode Lerang, Dmitry S Bordin, Vincent Lamy, Lisette G Capelle, Wojciech Marlicz, Daniela Dobru, Oleksiy Gridnyev, Ignasi Puig, Francis Mégraud, Colm O'Morain, Javier P Gisbert
Journal: Gut (2022)

Objective To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe. Design International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis. Results Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed &gt;90% of cases. Overall effectiveness remained &lt;90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p&lt;0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted ≥14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%. Conclusion Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update. Trial registration number NCT02328131 .
Trends and Disparities in Stage-Specific Incidence of Hepatocellular Carcinoma among US Adults, 2004–2019
Authors: Haoting Shi, Jingxuan Huang, Shi Zhao, Yiwen Jin, Rong Cai, Jinjun Ran
Journal: Liver Cancer (2022)

Introduction: The aim of this study was to determine the stage-specific incidence trend of hepatocellular carcinoma (HCC) among US adults. Methods: The age-adjusted incidence rate was extracted from Surveillance, Epidemiology, and End Results database for localized, regional, and distant HCC. Trend analyses were conducted in the overall population and stratified by demographic and sociodemographic variables. The annual percentage change (APC) in 2014–2019 was estimated to determine the stage-specific incidence trend. Results: Although the incidence of localized HCC significantly declined, the incidence for regional and distant HCC plateaued in 2014–2019 (APCs, 4.4% [95% CI, −0.2% to 9.3%] and −0.7% [95% CI, −1.8% to 0.5%], respectively) with age and race/ethnicity disparities. More pronounced increases for regional and distant HCC were observed among the elderly (APCs, 8.4% [95% CI, 4.8–12.2%] and 2.2% [95% CI, 1.7–2.7%] for regional and distant HCC, respectively), non-Hispanic white individuals (APCs, 4.0% [95% CI, 2.9–5.1%] and 1.5% [95% CI, 0.7–2.4%] for regional and distant HCC, respectively). Conclusions: Disparities in incidence trends may reflect the inequalities in access to primary health care. More efforts are still in great demand for the vulnerable population.
In generally healthy adults, supplemental vitamin D<sub>3</sub> did not reduce fractures vs. placebo at 5 y
Authors: Kristine E. Ensrud
Journal: Annals of Internal Medicine (2022)

ACP Journal ClubDecember 2022In generally healthy adults, supplemental vitamin D3 did not reduce fractures vs. placebo at 5 yKristine E. Ensrud, MD, MPHKristine E. Ensrud, MD, MPHUniversity of Minnesota and Minneapolis VA Health Care System, Minneapolis, Minnesota, USA (K.E.E.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/J22-0099 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387:299-309. https://pubmed.ncbi.nlm.nih.gov/35939577Clinical Impact RatingsGIM/FP/GP: Endocrinology: References1. Mishra S, Stierman B, Gahche JJ, et al. Dietary supplement use among adults: United States, 2017-2018. NCHS Data Brief. 2021;(399):1-8. [PMID: 33663653] Google Scholar2. LeBoff MS, Murata EM, Cook NR, et al. VITamin D and OmegA-3 TriaL (VITAL): effects of vitamin D supplements on risk of falls in the US population. J Clin Endocrinol Metab. 2020;105:2929-38. [PMID: 32492153] Google Scholar3. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380:33-44. [PMID: 30415629] Google Scholar4. Kahwati LC, LeBlanc E, Weber RP, et al. Screening for vitamin D deficiency in adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021;325:1443-63. [PMID: 33847712] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Minnesota and Minneapolis VA Health Care System, Minneapolis, Minnesota, USA (K.E.E.)Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J22-0099.This article was published at Annals.org on 6 December 2022.ACP Journal Club is editorially independent from Annals of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics December 2022Volume 175, Issue 12Page: JC134KeywordsBone fractureCardiovascular diseasesFallsFatty acidsLiver diseasesOsteoporosisPopulation statisticsRenal failureVitamin DVitamin D deficiency ePublished: 6 December 2022 Issue Published: December 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Spatiotemporal Regulation of Injectable Heterogeneous Silk Gel Scaffolds for Accelerating Guided Vertebral Repair
Authors: Tianji Wang, Keyin Liu, Jing Wang, Geng Xiang, Xiaofan Hu, Hao Bai, Wei Lei, Tiger H. Tao, Yafei Feng
Journal: Advanced Healthcare Materials (2022)

Abstract Osteoporotic vertebral fracture is jeopardizing the health of the aged population around the world, while the hypoxia microenvironment and oxidative damage of bone defect make it difficult to perform effective tissue regeneration. The balance of oxidative stress and the coupling of vessel and bone ingrowth are critical for bone regeneration. In this study, an injectable heterogeneous silk gel scaffold which can spatiotemporally and sustainedly release bone mesenchymal stem cell‐derived small extracellular vesicles, HIF‐1 α pathway activator, and inhibitor is developed for bone repair and vertebral reinforcement. The initial enhancement of HIF‐1 α upregulates the expression of VEGF to promote angiogenesis, and the balance of reactive oxygen species level is regulated to effectively eliminate oxidative damage and abnormal microenvironment. The subsequent inhibition of HIF‐1 α avoids the overexpression of VEGF and vascular overgrowth. Meanwhile, complex macroporous structures and suitable mechanical support can be obtained within the silk gel scaffolds, which will promote in situ bone regeneration. These findings provide a new clinical translation strategy for osteoporotic vertebral augmentation on basis of hypoxia microenvironment improvement.